Among the active constituents of nature medicine, proteins, polypeptides, terpenoids, steroids, alkaloids, flavonoids, anthraquinones, and phenylpropanoid phenols all show various effective properties in the term of biologically activity, and therefore, they've been widely used in medicine. Their glycoside, nucleoside and polypeptide derivatives have also shown considerable applications. As natural active constituents, they have the advantages of fast biodegradation rate, little or no residue, low toxicity, and little or no side effects. However, they still have some disadvantages such as low bioavailability, short physiological half-life, poor water solubility, immunogenecity and the like.
To solve the problems, the derivatives of PEG have been widely used to conjugate with proteins, peptides or other therapeutic agents in order to prolong their physiological half-life and to lower their immunogenicity and toxicity. Clinically, PEG and its derivatives have been widely used as carrier to manufacture preparations of commercial drugs. And the attempt of conjugating PEG to drug molecule has an impressive progress in the last 10 years and has been applied to many officially approved drugs. For example, PEG-intron®, a conjugate of PEG and α-interferon, exhibits longer circulation half-life and better therapeutic effect compared to the native form of α-interferon. It has been shown that the conjugate of PEG and paclitaxel correspondingly reduces the toxicity and prolongs the bioactivity. The metabolism processes of these conjugate are well known, showing that PEG is a safe drug modifier.
When conjugating PEG to drugs, often is used a process called as PEGylation, in which one or two of the terminal groups of PEG are chemically activated to have a proper functional group which is reactive to at least one functional group of the drug to form a stable bond. This stable bond can be eliminated by degradation under proper conditions in vivo, and thereby the active ingredient is released.
It's reported that PEG can be used to conjugate to many drugs. The prodrugs of PEG derivatives conjugating with paclitaxel have been disclosed in U.S. Pat. Nos. 5,824,701 and 5,840,900 and CN patent CN1283643. In these patents, each of the two terminal groups of PEG is conjugated with a paclitaxel molecule. In order to increase the drug molecule load, U.S. Pat. No. 6,153,655 discloses a terminally branched PEG structure, in which two functional groups are formed via amino linkage at the two termini of PEG. However, the introduction of non-biological branched small molecule also makes the drug property indefinite. U.S. Pat. Nos. 5,977,163 and 6,262,107 and Chinese patent CN1164533 disclose a paclitaxel prodrug with polyglutamic acid as carrier, in which paclitaxel is attached randomly to the active carboxyl groups of glutamic acid along the polyglutamic acid skeleton. The broad polydispersity and uncertainty of the toxicity of polyglutamic acid limit the application of these inventions.